Absolute configuration of (+)-[fluoro(hydroxyphenylphosphinyl)methyl]-phosphonic acid, a specific inhibitor of Na(+)-gradient-dependent Na(+)-phosphate cotransport across renal brush border membrane, by X-ray crystallographic analysis of its (-)-quinine salt

J Med Chem. 1995 Apr 28;38(9):1575-8. doi: 10.1021/jm00009a018.

Abstract

Racemic [fluoro(hydroxyphenylphosphinyl)methyl]phosphonic acid (1) and its individual enantiomers [(+), 98% ee; (-), 67% ee] were previously shown to inhibit Na(+)-gradient-dependent Na(+)-phosphate cotransport across renal brush border membrane, without measurable stereospecificity. Resolution of 1 was effected by fractional recrystallization of its (-)-quinine salts. The more levorotatory, diquinine product 2, corresponding to (+)-1, has now been analyzed by X-ray crystallography and found to be composed of the S enantiomer of 1. This result confirms the absence of stereochemical preference in inhibition of the cotransporter by the enantiomers of 1 and provides the first absolute configuration assignment of an asymmetrical alpha-halomethylene pyrophosphate analogue.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carrier Proteins / drug effects*
  • Crystallography, X-Ray
  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacology
  • Kidney / drug effects*
  • Kidney / metabolism
  • Magnetic Resonance Spectroscopy
  • Microvilli / drug effects
  • Microvilli / metabolism
  • Molecular Conformation
  • Quinine / chemistry
  • Salts
  • Sodium / metabolism*
  • Sodium-Phosphate Cotransporter Proteins
  • Symporters*

Substances

  • (fluoro(hydroxyphenylphosphinyl)methyl)phosphonic acid
  • Carrier Proteins
  • Diphosphonates
  • Salts
  • Sodium-Phosphate Cotransporter Proteins
  • Symporters
  • Sodium
  • Quinine